Hypothalamic obesity occurs subsequent to or in association with a pathological process injuring the hypothalamus. This syndrome is characterized by rapid, unrelenting weight gain that may be accompanied by severe hyperphagia. Weight gain of hypothalamic obesity is unlike that of normal obesity in that occurs even with caloric restriction. For example, following a hypothalamic lesion, patients develop a voracious hyperphagia that is hard to contain. Further, hypothalamic obesity is typically not responsive to diet and exercise.
Hypothalamic obesity can occur with any damage to or defect of the energy controlling centers of the hypothalamus. In particular, hypothalamic obesity is an unfortunate complication in some survivors of brain tumors, especially those diagnosed in childhood. It has been estimated that up to 75% of all survivors of craniopharyngioma develop severe obesity after diagnosis and treatment, with body weight rapidly accelerating after surgical resection of the tumor.
Hypothalamic obesity can also occur with genetic syndromes, such as in patients having mutations in leptin or leptin receptor, CART (cocaine and amphetamine-related transcript), POMC (proopiomelanocorgin), prophormone convertase, MC4R (melanocortin-4 receptor), singleminded 1 (a transcription factor essential for formation of the supraoptic and PVN nuclei in the hypothalamus), and TrkB. Prader-Willi syndrome, caused by deletion of paternally imprinted genes on chromosome 15q11-q13 and BBS (Bradet-Biedl syndrome) can also cause hypothalamic obesity. Further, many psychotropic drugs, for example, clozapine and olanzapine lead to hypothalamic-like obesity.
The hypothalamus regulates body weight by precisely balancing the intake of food, energy expenditure and amount of body fat tissue. The main hypothalamic areas involved in energy regulation (that when damaged cause hypothalamic obesity) include the ventromedial hypothalamus, paraventricular nuclei, arcuate nucleus and the lateral hypothalamic area. Further, signals from fat tissue mass in the body (including leptin) and from the gastrointestinal tract (including g GLP-1, PYY, and/or pancreatic insulin/amylin), affect the hypothalamic centers. Disorders involving any these type signals interaction with the hypothalamus, or damage to the hypothalamus, can lead to morbid, hypothalamic obesity. Weight gain occurs from the disruption of the normal homeostatic functioning of the hypothalamic centers, with loss of control of satiety and hunger, inability to regulate energy balance, reduction of energy expenditure, and/or hyperinsulinemia and frequent progression to diabetes. In contrast, “simple” obesity seems to result from patient variability in environmental cues, psychological/emotional status, and/or weight-regulating mechanisms.
Despite some understanding of the mechanism of hypothalamic obesity, treatment for hypothalamic obesity remains unsatisfactory and largely lacking, in part because there is an absence of well-established preventative or therapeutic strategies. Furthermore, hypothalamic obesity confers significant morbidity and mortality with a serious lack negative impact on those, for example, family members, who car for these patients.